DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Formal Matters
Applicant’s amendments and arguments filed on 01 April 2026 are acknowledged and have been fully considered. Claims 12, 25-27, and 29-40 are pending. Claims 25-27, 29, 31, 33-34, and newly added claims 35-40 are under consideration in the instant office action. Claims 12, 30 and 32 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claims. Claims 1-11, 13-24, and 28 are cancelled.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections-maintained
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Note: The claims are examined with regard to the elected species only.
Claims 25, 27, 29, 31, 33-34, and newly added claims 35-40 are rejected under 35 U.S.C. 103 as being unpatentable over BHAGAVAN (Medical Biochemistry (Fourth Edition), pages 197-224, 2002, previously cited) in view of Stern (US 2005/0112178, previously provided)
Applicants’ claims
Applicants claims a method of measuring phospholipid (PL), phospholipid bound fatty acids, free fatty acids, arachidonic acid (AA), AA precursors, fatty acid metabolites, choline, lipids, and/or triglyceride quantities in a fecal sample from a human patient. Applicant amended claims 25 and 34 by utilizing the transitional phrase “consisting essentially of” in the recitation of step ii. Dependent claims thereof recite other features.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
BHAGAVAN teaches the gastrointestinal (or alimentary) system (or tract) is responsible for digestion and absorption of nutrients and fluids. The tract extends from the mouth to the anus and in an adult human is about 10 m long. Digestion is the hydrolysis of complex food substances into simpler units such as monosaccharides, amino acids, fatty acids, and glycerol. Absorption is the transport of the products of digestion and of vitamins, minerals, and water across the intestinal epithelium to the lymphatic or blood circulatory systems. Digestion and absorption involve not only the gastrointestinal (GI) tract but also secretions from salivary glands, liver (and gallbladder), and pancreas. These processes in the GI system are interrelated. The system provides highly selective, efficient, and elaborate absorptive surfaces that contain enzymes and secretions of enzyme-containing fluids, electrolytes, and other substances required for digestion and absorption. Secretory and absorptive activities are regulated by hormonal and neural mechanisms (see page 197). BHAGAVAN teaches Dietary fat provides energy in a highly concentrated form and accounts for 40--45% of the total daily energy intake (100 g/day in the average Western diet). Lipids contain more than twice the energy per unit mass than carbohydrates and proteins (Chapter 5). The efficiency of fat absorption is very high; under normal conditions, almost all ingested fat is absorbed, with less than 5% appearing in the feces. The predominant dietary lipid is triacylglycerol (previously called triglyceride), which contains three long-chain (16-carbon or longer) fatty acids (Chapter 18). The dietary lipids include essential fatty acids (Chapter 18) and the lipid-soluble vitamins A, D, E, and K (Chapters 36-38). Digestion and absorption of lipids involves the coordinated function of several organs but can be divided into three phases: luminal, intracellular, and secretory (page 216). The hydrolysis of triacylglycerol in the duodenum and jejunum requires bile and pancreatic juice. Bile acids are powerful detergents that, together with monoacylglycerol and phosphatidylcholine, promote the emulsification of lipids. Emulsification is also aided by the churning action of the GI tract which greatly increases the area of the lipid-water interface that promotes the action of pancreatic lipase. This triacylglycerol lipase hydrolyzes ester linkages at the 1- and 3-positions to yield 2-monoacylglycerol and fatty acids (Figure 12-13). The products of digestion are relatively insoluble in water but are solubilized in micelles. Micelles also contain lipid soluble vitamins, cholesterol, and phosphatidylcholine (see page 217). BHAGAVAN teaches under the section disorders of lipid digestion and absorption on page 218 normally more than 95% of ingested lipid is absorbed. When a large fraction is excreted in the feces, it is called steatorrhea. Measurement of fecal lipid with adequate lipid intake is a sensitive indicator of lipid malabsorption. Malabsorption can result from impairment in lipolysis (Table 12-6), micelle formation (Table 12-7), absorption, chylomicron formation, or transport of chylomicrons via the lymph to blood. The examiner notes that physiological amounts of lipids, fatty acids, etc., is conventionally available as standard in lipid profile tests which is used as a standard.
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Lipid absorption in the duodenum and jejunum appears to be a passive diffusion process. Lipid-laden micelles migrate to the microvilli, and the fatty acids, monoacylglycerols, and lysophosphoglycerols are transferred across the membrane according to their solubility within the lipid bilayer of the cell surfaces (page 217). The examiner indicates that BHAGAVAN clearly teaches that Measurement of fecal lipid with adequate lipid intake is a sensitive indicator of lipid malabsorption. Malabsorption can result from impairment in lipolysis (Table 12-6), micelle formation (Table 12-7), absorption, chylomicron formation, or transport of chylomicrons via the lymph to blood. BHAGAVAN clearly as described above BHAGAVAN teaches Dietary fat provides energy in a highly concentrated form and accounts for 40--45% of the total daily energy intake (100 g/day in the average Western diet). BHAGAVAN as described above teaches the formation micelles. BHAGAVAN also teaches Vesicles that contain chylomicrons synthesized within the endoplasmic reticulum and the saccules of the Golgi apparatus migrate toward the laterobasal membrane, fuse with it, and extrude the chylomicrons into the interstitial fluid, where they enter the lymphatic vessels through fenestrations. Medium-chain triacylglycerols are absorbed and transported by portal blood capillaries without formation of micelles or chylomicrons. Chylomicrons enter the bloodstream at the left subclavian vein via the thoracic duct. In the bloodstream, they are progressively hydrolyzed by endothelial lipoprotein lipase activated by apolipoprotein C-II. Fatty acids so released are taken up by the tissues (e.g., muscle and adipose) as blood passes through them. The chylomicron remnants consist primarily of lipid-soluble vitamins and cholesterol (and its esters) and are metabolized in the liver. Chylomicrons normally begin to appear in the plasma within 1 hour after ingestion of fat and are completely removed within 5-8 hours (see Chapters 18-20) (see page 218). BHAGAVAN teaches 100g/day intake of lipid and the measurement of fecal lipids to determine malabsorption. Although BHAGAVAN teach the formation of micelles, BHAGAVAN is silent with regard to the formation of sequestered and aggregated mixed micelles and vesicles (SAMMVs). Since BHAGAVAN performs the same steps as the claimed method which is administration of an oral dose of lipid, the formation of sequestered and aggregated mixed micelles and vesicles (SAMMVs) would necessarily and inherently happen. "[I]nherency may supply a missing claim limitation in an obviousness analysis." PAR, 773 F.3d at 1194-1195 ; see also Endo Pharms. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374 , 1381 , 127 U.S.P.Q.2D (BNA) 1409 (Fed. Cir. 2018) ("An inherent characteristic of a formulation can be part of the prior art in an obviousness analysis even if the inherent characteristic was unrecognized or unappreciated by a skilled artisan."). It is long settled that in the context of obviousness, the "mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not distinguish a claim drawn to those things from the prior art." In re Oelrich, 666 F.2d 578 , 581 (C.C.P.A. 1981). The Supreme Court explained long ago that "[i]t is not invention to perceive that the product which others had discovered had qualities they failed to detect." Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242 , 249 , 66 S. Ct. 81 , 90 L. Ed. 43 , 1946 Dec. Comm'r Pat. 611 (1945). We too have previously explained that "an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations," because "[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property." Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 , 1354 (Fed. Cir. 2012). In In re Kao, we found that the claimed controlled-release oxymorphone formulation was obvious because an inherent pharmacokinetic property of oxymorphone that was present in controlled-release oxymorphone "add[ed] nothing of patentable consequence." In re Huai-Hung Kao, 639 F.3d 1057 , 1070 , 98 U.S.P.Q.2D (BNA) 1799 (Fed. Cir. 2011). In In re Kubin, we found an inherent property obvious, explaining that "[e]ven if no prior art of record explicitly discusses the [limitation], the . . . application itself instructs that [the limitation] is not an additional requirement imposed by the claims on the [claimed protein], but rather a property necessarily present in [the claimed protein]." In re Kubin, 561 F.3d 1351 , 1357 , 90 U.S.P.Q.2D (BNA) 1417 (Fed. Cir. 2009). Our predecessor court similarly concluded that it "is not the law" that "a structure suggested by the prior art, and, hence, potentially in the possession of the public, is patentable . . . because it also possesses an [i]nherent, but hitherto unknown, function which [the patentees] claim to have discovered." In re [*1191] Wiseman, 596 F.2d 1019 , 1023 (C.C.P.A. 1979). Inherency, however, is a "high standard," that is "carefully circumscribed in the context of obviousness." PAR, 773 F.3d at 1195 . Inherency "may not be established by probabilities or possibilities," and "[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Oelrich, 666 F.2d at 581 (emphasis added) (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939); see also In re Rijckaert, 9 F.3d 1531 , 1533-1534 (Fed. Cir. 1993). Rather, inherency renders a claimed limitation obvious only if the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the prior art." PAR, 773 F.3d at 119511 -96; see also Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 , 1369 (Fed. Cir. 2012) (relying on inherency where the claims recited "a property that is necessarily present" in the prior art). "If . . . the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient" to render the function inherent. Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939)). On appeal, Persion contends that the district court erred in applying the inherency doctrine in its obviousness analysis because Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment. Thus, Persion asserts, "'the natural result flowing from the operation as taught' in Devane cannot be the claimed [pharmacokinetic] values for [hepatically impaired] patients." Appellant's Br. 37 (quoting Oelrich, 666 F.2d at 581 ); Reply Br. 19. To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to our prior recognition that "inherency may supply a missing claim limitation in an obviousness analysis" where the limitation at issue is "the natural result of the combination of prior art elements." PAR, 773 F.3d at 1194-1195 (emphasis added, internal quotations omitted). Here, the district court specifically found that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters under these conditions. Pernix, 323 F. Supp. 3d at 607 , 610 . In this context, the district court did not err by finding that the pharmacokinetic limitations of the asserted claims were inherent and added no patentable weight to the pharmacokinetic claims.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
BHAGAVAN does not specifically teach the administration of a cathartic (magnesium). This deficiency is cured by the teachings of Stern.
Stern teaches this invention relates to a nutritional kit for use in preparing an individual for a predetermined activity which requires a clean digestive tract, particularly the colon. Such predetermined activities include, but are not limited to, gastrointestinal surgery and colon screenings. Specifically, the present invention provides an individual low amounts of fat, dietary fiber and solid food content to minimize stool formation and/or facilitate removal of stool from the digestive tract prior to the predetermined activity. The present invention also provides the individual with sufficient calories and nutrition to enable the individual to conduct daily, routine activities while utilizing the present invention. In one alternative embodiment, the present kit provides a variety of pre-packaged, ready to eat or easy to prepare nutritional liquid or solid foods which when coordinated with a laxative regimen, result in removal of residue such that a medically and/or diagnostically useful procedure can be performed on the digestive tract (see abstract). Generally, two procedures are used to remove stool matter from the digestive tract in preparation for surgery or a colon screening. These regimens include: (1) pharmaco-mechanical preparations and (2) antibiotic preparations. Pharmaco-mechanical preparations involve taking drugs that cause the expulsion of the digestive tract's contents in the form of stool and/or diarrhea. An example of such a preparation is a large volume preparation such as Golytely.™, which requires drinking large volumes to physically flush at least some food residue out of the gastrointestinal tract. Another example of such a preparation is a smaller volume preparation such as Fleet.™ Phospho-Soda or magnesium citrate, which are saline-cathartic agents that pull additional fluid from the body to physically flush at least some food residue out of the gastrointestinal tract. Other pharmaco-mechanical preparations include bisacodyl tablets, suppositories or enemas, which work by stimulating peristalsis, i.e., by acting on smooth muscle to cause contractions that physically push food residue out of the gastrointestinal tract (paragraph 0011). In an alternative embodiment, the individual food items of the present invention may collectively provide vitamins and minerals in a range of at least 10% to about 100% USRDA over about a 20- to 36-hour period prior to a predetermined activity. Such vitamins and minerals, may include, for example, vitamins A, B.sub.1, B.sub.2, B.sub.3, B.sub.6, B.sub.12, C, D, E, and K, Biotin, Calcium, Copper, Chromium Folic Acid, Iodine, Iron, Magnesium, Manganese, Niacin, Pantothenic Acid, Phosphorus, Riboflavin, Thiamin and Zinc. Also, each of the individual food items may contain or be fortified in such a way as to provide at least approximately 25% USRDA, and up to 100% USRDA of vitamins and minerals (paragraph 0070). An advantage of the present dietary regimen is that it facilitates the efficacy of a laxative regimen such that milder laxative regimens may be used. For example, PEG laxatives, such as Colyte.™ and Golytely.™, may be too strong or harsh for some individuals. This is so because these laxatives require the consumption of a high volume of unpalatable solution containing the cathartic agent over a short period of time. Also, consumption of such large amounts of fluid may induce gagging or vomiting in some individuals. Similarly, some saline laxatives containing sodium phosphate, such as Fleet.RTM, are considered by some individuals as bad-tasting. In contrast, magnesium citrate-based laxatives are considered better tasting than most purgative drinks. Also, magnesium citrate-based laxatives are generally considered more mild because they require the intake of fluid, usually water, over time. A further benefit of magnesium citrate-based laxatives is that they contain a comparably lower sodium content (paragraph 0128).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of BHAGAVAN by administration of a cathartic because Stern teaches this invention relates to a nutritional kit for use in preparing an individual for a predetermined activity which requires a clean digestive tract, particularly the colon. Such predetermined activities include, but are not limited to, gastrointestinal surgery and colon screenings. Specifically, the present invention provides an individual low amounts of fat, dietary fiber and solid food content to minimize stool formation and/or facilitate removal of stool from the digestive tract prior to the predetermined activity. The present invention also provides the individual with sufficient calories and nutrition to enable the individual to conduct daily, routine activities while utilizing the present invention. One of ordinary skill in the art would have been motivated to do so because Stern teaches in one alternative embodiment, the present kit provides a variety of pre-packaged, ready to eat or easy to prepare nutritional liquid or solid foods which when coordinated with a laxative regimen, result in removal of residue such that a medically and/or diagnostically useful procedure can be performed on the digestive tract (see abstract). Generally, two procedures are used to remove stool matter from the digestive tract in preparation for surgery or a colon screening. These regimens include: (1) pharmaco-mechanical preparations and (2) antibiotic preparations. Pharmaco-mechanical preparations involve taking drugs that cause the expulsion of the digestive tract's contents in the form of stool and/or diarrhea. An example of such a preparation is a large volume preparation such as Golytely.™, which requires drinking large volumes to physically flush at least some food residue out of the gastrointestinal tract. Another example of such a preparation is a smaller volume preparation such as Fleet.™ Phospho-Soda or magnesium citrate, which are saline-cathartic agents that pull additional fluid from the body to physically flush at least some food residue out of the gastrointestinal tract. Other pharmaco-mechanical preparations include bisacodyl tablets, suppositories or enemas, which work by stimulating peristalsis, i.e., by acting on smooth muscle to cause contractions that physically push food residue out of the gastrointestinal tract (paragraph 0011). In an alternative embodiment, the individual food items of the present invention may collectively provide vitamins and minerals in a range of at least 10% to about 100% USRDA over about a 20- to 36-hour period prior to a predetermined activity. Such vitamins and minerals, may include, for example, vitamins A, B.sub.1, B.sub.2, B.sub.3, B.sub.6, B.sub.12, C, D, E, and K, Biotin, Calcium, Copper, Chromium Folic Acid, Iodine, Iron, Magnesium, Manganese, Niacin, Pantothenic Acid, Phosphorus, Riboflavin, Thiamin and Zinc. Also, each of the individual food items may contain or be fortified in such a way as to provide at least approximately 25% USRDA, and up to 100% USRDA of vitamins and minerals (paragraph 0070). An advantage of the present dietary regimen is that it facilitates the efficacy of a laxative regimen such that milder laxative regimens may be used. For example, PEG laxatives, such as Colyte.™ and Golytely.™, may be too strong or harsh for some individuals. This is so because these laxatives require the consumption of a high volume of unpalatable solution containing the cathartic agent over a short period of time. Also, consumption of such large amounts of fluid may induce gagging or vomiting in some individuals. Similarly, some saline laxatives containing sodium phosphate, such as Fleet.RTM, are considered by some individuals as bad-tasting. In contrast, magnesium citrate-based laxatives are considered better tasting than most purgative drinks. Also, magnesium citrate-based laxatives are generally considered more mild because they require the intake of fluid, usually water, over time. A further benefit of magnesium citrate-based laxatives is that they contain a comparably lower sodium content (paragraph 0128). It is to be noticed that one of ordinary skill in the art would know to clean the intestine before diagnosis testing in order to avoid false results from other sources. An ordinary skilled artisan would have had a reasonable chance of success in combining the teachings of BHAGAVAN and Stern because both references teach diagnosis of conditions that need cleaning gastrointestinal tract before testing. In the case where the claimed range of amounts of ingredients "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are teach in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over BHAGAVAN (Medical Biochemistry (Fourth Edition), pages 197-224, 2002, newly cited) in view of Stern (US 2005/0112178, previously provided) as applied to claims 25, 27, 29, 31, and 33-40 above, and further in view of Nyberg et al. (J. Nutr. Biochem. 11:244-249, 2000, newly cited).
Applicants’ claims
Applicants claims A method of measuring phospholipid (PL), phospholipid bound fatty acids, free fatty acids, arachidonic acid (AA), AA precursors, fatty acid metabolites, choline, lipids, and/or triglyceride quantities in a fecal sample from a human patient. Claim 26 recites the method of claim 25, further requiring the patient to fast for a period of 24 or more hours before administration of the oral dose.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of BHAGAVAN and Stern are set forth above and are incorporated herein by reference.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
BHAGAVAN and Stern do not specifically teach the method of claim 25, further requiring the patient to fast for a period of 24 or more hours before administration of the oral dose as recited in claim 26. This deficiency is cured by the teachings of Stern.
Nyberg et al. teach several studies have shown that there is a strong physical interaction between cholesterol and sphingomyelin (SM). The critical factor is thought to be the high degree of saturation in the very long acyl chains of SM. In this study we examined the effects of SM on cholesterol absorption in the rat and compared them with those of phosphatidylcholine (PC). Cholesterol absorption was studied by use of the dual-isotope plasma ratio method. We also studied the effect of sterols on the fecal excretion of undigested SM and its metabolites after a single oral meal of 3 H-dihydrosphingosine-labeled SM. When cholesterol was given dissolved in soybean oil, without addition of SM or other phospholipids, absorption was 68 ± 12% in the rat intestine. As a general feature the absorption was less efficient from the cholesterol/phospholipid dispersions. In dispersions with cholesterol and SM, the lowest cholesterol absorption (9 ± 2%) was seen with a cholesterol:SM molar ratio of 1:1. With dispersions of cholesterol and different PC substrates the absorption of cholesterol was lower with saturated PC (16±8%) than with soybean-PC (22 ± 4%) or dioleoyl PC (23 ± 8%). Uptake of SM in the rat intestine was reduced by sterols. For example, percentage recovery of 3 H radioactivity in fecal lipids was 38 ±8% when SM was given with cholesterol and 16 ± 3% without any sterol. One third of the radioactivity in feces was present as ceramide. Sitostanol had the same effect on uptake of SM as cholesterol. This study shows that when rats are fed mixtures of SM and cholesterol the intestinal uptake of both lipids is decreased. By feeding mixtures of SM and sterols the exposure of the colon to ceramide can be increased (see abstract). Nyberg et al. teach before the experiments rats were fasted for 24 hr, with free access to tap water. The rats were anesthetized lightly with diethyl ether and fed 3 mL of the dispersions (0.5 mL of the dispersion with soybean oil) described above by gastrogavage. All oral dispersions were prepared the afternoon before. On the day of experiments each dispersion was sonicated an additional 1.5 min (see page 246). In rats given dispersions with 3 H-SM, lipids were extracted from the feces with chloroform:methanol:water, according to the method of Bligh and Dyer.18 Aliquots of the chloroform phase were taken for liquid scintillation counting. On plates of silica gel (Merck, Si 60-F; 0.25 mm) (Merck Ltd., Dorset, United Kingdom), aliquots of the chloroform phase were taken for TLC analysis. The plates were developed in chloroform:methanol:ammonia (100:15: 1.5, v/v/v), which separates SM and its hydrolysis products ceramide, sphingosine, fatty acid, and triglyceride. In this solvent system SM and other phospholipids remain at the start, while triglycerides migrate with the front. Rf values for sphingosine and ceramide were 0.3 and 0.7, respectively. Free fatty acids with an Rf value of 0.1 are included in polar lipids in the presentation of results.
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of BHAGAVAN and Stern by further requiring the patient to fast for a period of 24 or more hours before administration of the oral dose because Nyberg et al. teach several studies have shown that there is a strong physical interaction between cholesterol and sphingomyelin (SM). The critical factor is thought to be the high degree of saturation in the very long acyl chains of SM. In this study we examined the effects of SM on cholesterol absorption in the rat and compared them with those of phosphatidylcholine (PC). Cholesterol absorption was studied by use of the dual-isotope plasma ratio method. We also studied the effect of sterols on the fecal excretion of undigested SM and its metabolites after a single oral meal of 3 H-dihydrosphingosine-labeled SM. When cholesterol was given dissolved in soybean oil, without addition of SM or other phospholipids, absorption was 68 ± 12% in the rat intestine. As a general feature the absorption was less efficient from the cholesterol/phospholipid dispersions. In dispersions with cholesterol and SM, the lowest cholesterol absorption (9 ± 2%) was seen with a cholesterol:SM molar ratio of 1:1. With dispersions of cholesterol and different PC substrates the absorption of cholesterol was lower with saturated PC (16±8%) than with soybean-PC (22 ± 4%) or dioleoyl PC (23 ± 8%). Uptake of SM in the rat intestine was reduced by sterols. For example, percentage recovery of 3 H radioactivity in fecal lipids was 38 ±8% when SM was given with cholesterol and 16 ± 3% without any sterol. One third of the radioactivity in feces was present as ceramide. Sitostanol had the same effect on uptake of SM as cholesterol. This study shows that when rats are fed mixtures of SM and cholesterol the intestinal uptake of both lipids is decreased. By feeding mixtures of SM and sterols the exposure of the colon to ceramide can be increased (see abstract). Nyberg et al. teach before the experiments rats were fasted for 24 hr, with free access to tap water. One of ordinary skill in the art would have been motivated to do so by making the patient fast for 24 hours before consuming the oral lipid containing diet to increase the precision and accuracy of the measurements by avoiding the effect of any lipid in the gastrointestinal system that may interfere with the measurements. Nyberg et al. teach that the rats were anesthetized lightly with diethyl ether and fed 3 mL of the dispersions (0.5 mL of the dispersion with soybean oil) described above by gastrogavage. All oral dispersions were prepared the afternoon before. On the day of experiments each dispersion was sonicated an additional 1.5 min (see page 246). In rats given dispersions with 3 H-SM, lipids were extracted from the feces with chloroform:methanol:water, according to the method of Bligh and Dyer.18 Aliquots of the chloroform phase were taken for liquid scintillation counting. On plates of silica gel (Merck, Si 60-F; 0.25 mm) (Merck Ltd., Dorset, United Kingdom), aliquots of the chloroform phase were taken for TLC analysis. The plates were developed in chloroform:methanol:ammonia (100:15: 1.5, v/v/v), which separates SM and its hydrolysis products ceramide, sphingosine, fatty acid, and triglyceride. In this solvent system SM and other phospholipids remain at the start, while triglycerides migrate with the front. Rf values for sphingosine and ceramide were 0.3 and 0.7, respectively. Free fatty acids with an Rf value of 0.1 are included in polar lipids in the presentation of results. An ordinary skilled artisan would have had a reasonable chance of success in combining the teachings of BHAGAVAN, Stern, and Nyberg et al. because both BHAGAVAN and Nyberg teach the measurement of lipids after an oral lipid diet is administered to a biological subject while Sterns provide teachings before such tests cleaning the gastrointestinal system with a cathartic to clean the gastrointestinal tract. In the case where the claimed range of amounts of ingredients "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are teach in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 01 April 2026 have been fully considered but they are not persuasive.
Applicant argues the references (alone or in combination) fail to disclose or suggest steps (ii) and (iii), that there is no hint or suggestion of fecal SAMMV’s, and that there is no motivation to combine, mischaracterize the teachings of the references and the proper obviousness analysis. There is no hint or suggestion in Nyberg of sequestered and aggregated mixed micelles and vesicles (SAMMVs). There is no hint or suggestion in Nyberg of sequestered and aggregated mixed micelles and vesicles (SAMMVs) being excreted. There is no hint or suggestion in Nyberg of analysis of sequestered and aggregated mixed micelles and vesicles (SAMMVs) for phospholipids (PL).
The above assertions are not found persuasive because with regard to the disclosure or suggestion of steps (ii) and (iii) and fecal SAMMV’s Bhagavan is a standard medical biochemistry text book that comprehensively discusses lipid digestion, absorption, and the physicochemical behavior of lipids in the gastrointestinal tract. In the relevant pages as described above teaches, inter alia:
-Dietary triglycerides and phospholipids are emulsified and hydrolyzed by pancreatic lipases/phospholipases in the presence of bile salts.
-The products (fatty acids, monoacylglycerols, lysophospholipids, etc.) spontaneously form mixed micelles and vesicles with bile salts and phospholipids; these mixed micelles are the physiologic vesicles for lipid absorption in the small intestine.
-Not all lipids are absorbed; residual lipids, including phospholipid-bound fatty acids, free fatty acids, arachidonic acid and its precursors/metabolites, choline containing lipids, and triglycerides transit the lower GI tract and appear in feces. Measurement of fecal fat/lipid content is a classic clinical method for assessing malabsorption/steatorrhea.
Thus Bhagavan expressly teaches the formation of mixed micelles/vesicles from administered lipids and the subsequent recovery and analysis of residual lipids (including the exact classes recited in the claim) from feces. The coined acronym fecal SAMMV is simply a descriptive label for the very mixed micelle/vesicle structures that Bhagavan describes as arising from oral lipid administration and that reach the feces when absorption is incomplete or deliberately limited. A claim term that merely renames a known physiologic structure does not confer patentability. Stern teaches a nutritional kit and method for preparing a patient for a gastrointestinal procedure that requires a clean digestive tract. The kit/method comprises administering a low residue (including controlled lipid) diet together with one or more cathartics in amounts effective to evacuate the intestines, thereby minimizing residual stool and providing a clean baseline for subsequent diagnostic or therapeutic interventions. Stern therefore supplies the explicit teachings of step (i)-administration of an effective cathartic dose to evacuate the intestines-and the concept of controlled oral lipid intake in the context of bowel preparation. When the controlled oral lipid load of Bhagavan is administered after the cathartic evacuation taught by Stern, the natural and expected result is the formation of fecal mixed micelles/vesicles (SAMMV’s) whose phospholipid, fatty acid, arachidonic acid, choline, and triglyceride content can be analyzed exactly as claimed in steps (ii) and (iii). The claim language “consisting essentially of about 100± 30 grams lipids” is within the range of lipid loads routinely discussed in the biochemical literature for testing fat absorption and is therefore for testing fat absorptions and is therefore obvious selection of amount once the decision to administer a lipid challenge after bowl cleansing has been made. A person of ordinary skill in the art reading Bhagavan would have recognized the clinical utility of quantifying residual fecal lipids after a defined oral lipid challenge. Stern provides a practical, art recognized method of first clearing the bowel so that the subsequent fecal sample reflects only the administered test lipids rather than residual dietary material. The motivation is therefore the predictable desire to obtain a clean, standardized fecal specimen for accurate lipid analysis-the same motivation that underlies classical fecal fat tests and bowel preparation protocols. Combining a cathartic bowel prep regimen with a subsequent controlled lipid load followed by fecal lipid analysis is the ordinary application of known techniques to achieve a known clinical/diagnostic goal. The examiner indicates that BHAGAVAN clearly teaches that Measurement of fecal lipid with adequate lipid intake is a sensitive indicator of lipid malabsorption. Malabsorption can result from impairment in lipolysis (Table 12-6), micelle formation (Table 12-7), absorption, chylomicron formation, or transport of chylomicrons via the lymph to blood. BHAGAVAN clearly as described above BHAGAVAN teaches Dietary fat provides energy in a highly concentrated form and accounts for 40--45% of the total daily energy intake (100 g/day in the average Western diet). BHAGAVAN as described above teaches the formation micelles. BHAGAVAN also teaches Vesicles that contain chylomicrons synthesized within the endoplasmic reticulum and the saccules of the Golgi apparatus migrate toward the laterobasal membrane, fuse with it, and extrude the chylomicrons into the interstitial fluid, where they enter the lymphatic vessels through fenestrations. Medium-chain triacylglycerols are absorbed and transported by portal blood capillaries without formation of micelles or chylomicrons. Chylomicrons enter the bloodstream at the left subclavian vein via the thoracic duct. In the bloodstream, they are progressively hydrolyzed by endothelial lipoprotein lipase activated by apolipoprotein C-II. Fatty acids so released are taken up by the tissues (e.g., muscle and adipose) as blood passes through them. The chylomicron remnants consist primarily of lipid-soluble vitamins and cholesterol (and its esters) and are metabolized in the liver. Chylomicrons normally begin to appear in the plasma within 1 hour after ingestion of fat and are completely removed within 5-8 hours (see Chapters 18-20) (see page 218). BHAGAVAN teaches 100g/day intake of lipid and the measurement of fecal lipids to determine malabsorption. Although BHAGAVAN teach the formation of micelles, BHAGAVAN is silent with regard to the formation of sequestered and aggregated mixed micelles and vesicles (SAMMVs). Since BHAGAVAN performs the same steps as the claimed method which is administration of an oral dose of lipid, the formation of sequestered and aggregated mixed micelles and vesicles (SAMMVs) would necessarily and inherently happen. "[I]nherency may supply a missing claim limitation in an obviousness analysis." PAR, 773 F.3d at 1194-1195 ; see also Endo Pharms. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374 , 1381 , 127 U.S.P.Q.2D (BNA) 1409 (Fed. Cir. 2018) ("An inherent characteristic of a formulation can be part of the prior art in an obviousness analysis even if the inherent characteristic was unrecognized or unappreciated by a skilled artisan."). It is long settled that in the context of obviousness, the "mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not distinguish a claim drawn to those things from the prior art." In re Oelrich, 666 F.2d 578 , 581 (C.C.P.A. 1981). The Supreme Court explained long ago that "[i]t is not invention to perceive that the product which others had discovered had qualities they failed to detect." Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242 , 249 , 66 S. Ct. 81 , 90 L. Ed. 43 , 1946 Dec. Comm'r Pat. 611 (1945). We too have previously explained that "an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations," because "[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property." Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 , 1354 (Fed. Cir. 2012). In In re Kao, we found that the claimed controlled-release oxymorphone formulation was obvious because an inherent pharmacokinetic property of oxymorphone that was present in controlled-release oxymorphone "add[ed] nothing of patentable consequence." In re Huai-Hung Kao, 639 F.3d 1057 , 1070 , 98 U.S.P.Q.2D (BNA) 1799 (Fed. Cir. 2011). In In re Kubin, we found an inherent property obvious, explaining that "[e]ven if no prior art of record explicitly discusses the [limitation], the . . . application itself instructs that [the limitation] is not an additional requirement imposed by the claims on the [claimed protein], but rather a property necessarily present in [the claimed protein]." In re Kubin, 561 F.3d 1351 , 1357 , 90 U.S.P.Q.2D (BNA) 1417 (Fed. Cir. 2009). Our predecessor court similarly concluded that it "is not the law" that "a structure suggested by the prior art, and, hence, potentially in the possession of the public, is patentable . . . because it also possesses an [i]nherent, but hitherto unknown, function which [the patentees] claim to have discovered." In re [*1191] Wiseman, 596 F.2d 1019 , 1023 (C.C.P.A. 1979). Inherency, however, is a "high standard," that is "carefully circumscribed in the context of obviousness." PAR, 773 F.3d at 1195 . Inherency "may not be established by probabilities or possibilities," and "[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Oelrich, 666 F.2d at 581 (emphasis added) (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939); see also In re Rijckaert, 9 F.3d 1531 , 1533-1534 (Fed. Cir. 1993). Rather, inherency renders a claimed limitation obvious only if the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the prior art." PAR, 773 F.3d at 119511 -96; see also Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 , 1369 (Fed. Cir. 2012) (relying on inherency where the claims recited "a property that is necessarily present" in the prior art). "If . . . the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient" to render the function inherent. Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939)). On appeal, Persion contends that the district court erred in applying the inherency doctrine in its obviousness analysis because Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment. Thus, Persion asserts, "'the natural result flowing from the operation as taught' in Devane cannot be the claimed [pharmacokinetic] values for [hepatically impaired] patients." Appellant's Br. 37 (quoting Oelrich, 666 F.2d at 581 ); Reply Br. 19. To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to our prior recognition that "inherency may supply a missing claim limitation in an obviousness analysis" where the limitation at issue is "the natural result of the combination of prior art elements." PAR, 773 F.3d at 1194-1195 (emphasis added, internal quotations omitted). Here, the district court specifically found that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters under these conditions. Pernix, 323 F. Supp. 3d at 607 , 610 . In this context, the district court did not err by finding that the pharmacokinetic limitations of the asserted claims were inherent and added no patentable weight to the pharmacokinetic claims. Nyberg is solely added to render the limitation of claim 26. The argued elements are covered by Bhagavan and Stern as explained bove.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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